Potassium Phosphate, Tribasic → (+/-)-8-[5-(1-Ethoxycarbonyl-ethyl)-2-methoxy-phenyl]-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester

HRID 1773988Notes

Reaction equation

HRID 1773988 reaction equation
C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[CH2:30]([O:32][C:33](=[O:45])[CH:34]([C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[C:38](Br)[CH:37]=1)[CH3:35])[CH3:31].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH2:54]([O:61][C:62]([N:64]1[CH2:73][CH2:72][C:71]2[C:66](=[C:67](B3OC(C)(C)C(C)(C)O3)[CH:68]=[CH:69][C:70]=2[F:74])[CH2:65]1)=[O:63])[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1>C1(C)C=CC=CC=1.O.CCOCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:54]([O:61][C:62]([N:64]1[CH2:73][CH2:72][C:71]2[C:66](=[C:67]([C:38]3[CH:37]=[C:36]([CH:34]([C:33]([O:32][CH2:30][CH3:31])=[O:45])[CH3:35])[CH:41]=[CH:40][C:39]=3[O:42][CH3:43])[CH:68]=[CH:69][C:70]=2[F:74])[CH2:65]1)=[O:63])[C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1

Participants

9

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 112698722-Dicyclohexylphosphino-2',6'-dimethoxybiphenylHCID 574588042-(3-Bromo-4-methoxy-phenyl)-propionic acid ethyl esterHCID 896488855-fluoro-8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester

Product 1

HCID 89648690(+/-)-8-[5-(1-Ethoxycarbonyl-ethyl)-2-methoxy-phenyl]-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester

Reagents, catalysts & solvents 4

HCID 167845palladium(II) acetateCatalystHCID 962WaterSolventHCID 1140TolueneSolventHCID 3283Diethyl EtherSolvent

Conditions

Temperature
100 °C

Procedure

A mixture under N2 of palladium(II)acetate (1.2 mg, 5 μmol, 0.02 eq.), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (4.2 mg, 0.01 mmol, 0.04 eq.), (±)-2-(3-bromo-4-methoxy-phenyl)-propionic acid ethyl ester (80 mg, 0.26 mmol, 1 eq.) and potassium phosphate (109 mg, 0.51 mmol, 2 eq.) in toluene (1.9 mL) and water (0.2 mL) was stirred at r.t. during 2 min. 5-Fluoro-8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (147 mg, 0.26 mmol, 1 eq.) was added and the mixture was stirred at 100° C. for 18 hours. The mixture was allowed to cool to r.t., diluted with Et2O (10 mL), filtered through celite, washed with Et2O, and the filtrate was concentrated in vacuo. The residue was purified by prep. HPLC (column: Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to give the title compound as a colorless oil.

Workup

  1. temperatureto cool to r.t.
  2. filtrationfiltered through celite
  3. washwashed with Et2O
  4. concentrationthe filtrate was concentrated in vacuo
  5. customThe residue was purified by prep
  6. concentrationHPLC (column: Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo

Sources & evidence

ORD record
ord-d1c76907915f49adae84574116cc81b9
Source dataset
uspto-grants-2016_02
Patent number
US09255090B2

Reaction notes

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